Pancreatic cancer is one of the most lethal malignancies affecting Americans, and is considered largely incurable - according to the American Cancer Society, the one year survival rate (for all stages together) is 20% while the five-year survival rate is only 4%. This low survival rate is due to the difficulty in surgically removing the cancer at the time of diagnosis due to its spread. In 2012, about 43,920 Americans will be diagnosed with this cancer, and about 37,390 will die from it, according to the American Cancer Society. The existing chemotherapies and targeted therapies have not been satisfactory. Thus, there is a pressing and critical need to identify novel targets to develop therapies to treat this lethal cancer. This proposed R21 research effort will draw upon recent novel discovery by researchers at UAB (Drs. Yabing Chen and Jay McDonald) that showed that Fas activated the survival of pancreatic cancer cells through ERK activation in a FADD-independent manner, and involved the recruitment of tyrosine-protein kinase Src into the DISC (death-inducing signaling complex). Further, they showed that the activation of Src by calmodulin through its direct interaction with the c-Src-SH2 domain was responsible for the activation of ERK and pancreatic cancer cell survival. Based on these studies, we hypothesize that small molecule compounds that inhibit the interaction of the c-Src-SH2 domain with cellular CaM will also effectively inhibit the signaling pathway through which the pancreatic cancer cells escape apoptosis. Thus, these compounds will exhibit anti-pancreatic cancer activity. To test the above hypothesis, in this R21 application in response to PA-11-297 program (Pilot Studies in Pancreatic Cancer) we have identified the tyrosine kinase c-Src-SH2/calmodulin interaction as a novel therapeutic target for pancreatic cancer. The specific aim for the R21 application is to undertake structure-based identification of several small molecule compounds that specifically bind to the SH2 domain, inhibit the c-Src-SH2/calmodulin interaction, and exhibit anti-pancreatic activity in vitro. We will utilize molecular biology, high-field NMR spectroscopy, structure-based virtual screening of compound libraries, and functional assays using MiaPaCa-2 and BxPC-3 pancreatic cells to identify several promising small compounds with anti-pancreatic cancer activity. In future studies, some of these promising compounds will be further developed into leads and inhibitors with high anti-pancreatic cancer activity, low toxicity and favorable pharmacokinetic and pharmacodynamic profiles for testing in preclinical and clinical trials. Ultimately, the most successful inhibitors will play a significant role in the treatment of patient with pancreatic cancer.